The aim of this project is to characterize the function of Down syndrome critical region 1 (DSCR1) that is overexpressed in the brain of Down syndrome fetus. It belongs to a family of highly conserved proteins that bind and inhibit calcineurin, a phosphatase important for learning and memory, but its functional significance remains unclear. To investigate its physiological role, we generated a Drosophila mutant of nebula, an ortholog of human DSCR1. In this project we show that the nebula mutant shows enhanced calcineurin, but reduced PKA activities, and decreased level of phosphorylated cyclic AMP responsive element binding (CREB) protein. The nebula mutant also exhibits defective olfactory learning and long-term memory, while short-term memory remains intact. These results suggest that DSCR1 is required for learning and memory and that alteration of DSCR1 expression in the brain could be one of the possible underlying mechanisms of mental retardation in Down syndrome.